Synthesis of N4 donor Novel Schiff base ligands and their Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) metal complexes for biological studies and Catalytic oxidation on drug molecule

Hanmanthu Guguloth

Department of Chemistry, Kakatiya University, Warangal 506009, T.S., India

*Corresponding Author E-mail: hanmanthu.guguloth@yahoo.com

ABSTRACT:

Novel Schiff base ligands (N4 donor; L1–L2) have been derived from the condensation of O- phthalaldehyde (OPA) with some substituted aromatic amines, and subsequently used to synthesize the metal complexes of Co(II), Ni(II), Cu(II), Rh(III) and Pd(II). The structures of Schiff base ligands and their metal complexes were characterized by elemental analyses, IR, 1H and 13CNMR, mass and electronic spectroscopy, thermal, magnetic and conductance measurements. Both the ligands and their complexes have been screened for their antibacterial activities against Gram positive and Gram negative bacteria by MIC method and antifungal activities against Aspergillus flavus and Fusarium oxysporum. Further, these metal complexes have been investigated as catalysts in the oxidation of pharmaceutical drug didanosine. The oxidized products have further been treated with sulphanilic acid to develop the colored products to determine by spectrophotometrically. The current oxidation method is an environmentally friendly, simple to set-up, requires short reaction time, produces high yield and does not require co-oxidant.

KEYWORDS: O- phthalaldehyde, Schiff base ligands, Metal complexes, Antimicrobial activity, Catalytic oxidation.

INTRODUCTION:

Schiff bases and their transition metal complexes have enormously expanded subjects consisting of organometallic compounds and biocoordination chemistry. The design and synthesis of symmetrical Schiff bases derived from condensation of carbonyl compounds and amines. Schiff bases as well as their metal complexes have been of interest due to their preparative accessibility, structural variability and tunable electronic properties allowing to carry out systematic reactivity studies based on ancillary ligand modifications. Schiff bases has numerous applications such as anticancer, antibacterial, antifungal and other biological properties. Some of the Schiff bases are reported as chelating agents, analytical reagents and as catalysts for various functional group transformations.

Schiff bases can be synthesized from O-phthalaldehyde (OPA), due to the presence of two aldehyde groups in it. It is also used as an intermediate in the synthesis of pharmaceuticals and other organic compounds. Metal complexes of adenine (6-aminopurine) are involved in many bio-chemical reactions^1–5. Metal complexes of Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) ions with adenine and OPA have many biological applications and catalytic reactions^6,7.

Drug catalysis plays a crucial role in the industrial production of active pharmaceutical ingredients (APIs) and its process related impurities. Nowadays, regulatory authorities are paying critical attention on the identification and quantization of impurities in APIs in order to protect the patient against unwanted side effects. Recent studies described a designed approach and guidance for isolation, identification and synthesis process related impurities^8,9 and degradation products of APIs^10,11. Further, synthesis of these impurities is selective, typical, time-consuming and in some cases synthetic chemist has to put more effort on this than the major product. Several cases are found in literature^12,13, where these impurities are procured by preparative liquid chromatography, when their selective synthesis became difficult. Since, procurement of these impurities by preparative means is too expensive, the use of novel catalysts for their selective synthesis is one of the best alternatives.

Further selective oxidation of alcohols is extremely important in synthetic chemistry, since the resulting carbonyl derivatives, which are widely used as intermediates. Oxidation of alcohols requires either the presence of a co-oxidant¹⁴ or prolonged oxidation time¹⁵ leading to concomitant environmental problems. Hence, the development of efficient catalytic systems that will reduces the above problems. This led to the development of Pd (II) catalysts for the oxidation of didanosine (DDI) via alcoholic group leading to the formation of aldehydic product (impurities) in the absence of co-oxidant with lesser oxidation times. In the present manuscript reported non-template synthesis, spectral characterization, structure and binding modes of aromatic amino nitrogens (N₄ donor) ligands (L₁ and L₂) and their complexes of Co(II), Ni(II), Cu(II), Rh(II) and Pd(II). The antimicrobial activity of Schiff bases and their complexes were determined by the cup plate method and the minimum inhibitory concentration by liquid dilution method against Gram-positive bacteria (Bacillus subtilis), Gram-negative bacteria (Escherichia coli) and fungi (Aspergillus flavus and Fusarium Oxysporum)^16–18.

EXPERIMENTAL:

All the chemicals used were of analytical grade. Solvents have been purified and dried before use, according to the standard procedures. CoCl₂.6H₂O, NiCl₂.6H₂O, CuCl₂.2H₂O, RhCl₃.3H₂O, PdCl₂.2H₂O, O-phthalaldehyde, substituted aromatic amines, Adenine and other chemicals have been obtained from Aldrich, USA. All the other compounds are analytical grade products from Merck. The solvents have been distilled and stored over molecular sieves. The purity of the compounds have been checked by TLC using Merck 60F254 silica gel plates. The melting points of all the Schiff base compounds have been obtained on a Buchi-510 melting point apparatus. The percentages of carbon, hydrogen, nitrogen in Schiff base metal compounds have been determined using a Perkin–Elmer CHN analyzer. Conductance measurements have been done on 10^-3 M solution of compounds in dichloromethane at 25 °C using Digisun Digital conductivity meter model DL-909.

The IR spectra were recorded in KBr pellets on Perkin Elmer-283 spectrophotometer and the scanning rate was 6 min. in the range of 4000-200 cm^-1. UV-Visible spectra were recorded using Shimadzu UV-160A. Brucker WH 300 (200 MHz) and Varian Gemini (200 MHz) spectrometers were used for ¹H NMR and ¹³C NMR spectra respectively. CEC-21-110B, Finningan Mat 1210 and MICROMASS-7070 spectrometers operating at 70 eV using a direct inlet system were used for mass spectra and VG-Auto-Spec-M mass spectrometer was used for FAB mass spectra. The ESR spectra were recorded and Gouy balance calibrated with Hg[Co(NCS)₄] was used for the determination of magnetic susceptibilities of complexes in solid state at room temperature. Vibrating sample magnetometer has been employed for the above mentioned purpose when small amounts of the complexes are available. Diamagnetic corrections have been effected using Pascal's constant. TGA and DTA curves were recorded in Leeds and Northrup unit with Pt and Pt +10 % Rh thermocouples. Hot air oven (Instrument and equipment Pvt. Ltd., Mumbai), incubator (Instrument and Equipment Pvt. Ltd., Mumbai), laminar airflow unit (Claslaminar technologies Pvt. Ltd. Secunderabad), autoclave (Medica Instrument Mfg. Co., Mumbai) were used in the present investigations.

The 0.1 N hydrochloric acid solution was prepared by diluting 9.1 ml of conc. hydrochloric acid solution (Merck) to1000 ml with double distilled water. 0.1 M sulfanilic acid solution (Merck) was prepared by dissolving 1.071 g in 100 ml of double distilled water.

Drug solutions:

An accurately weighed amount of tablet powder equivalent to 100 mg of DDI was extracted separately with chloroform (4 x 25 ml) and filtered. The filtrate have been evaporated to dryness and the residue was dissolved in 100 ml of double distilled water to achieve a concentration of 1 mg/ml. This solution has been diluted with double distilled water to get the working standard stock solution of 100 μg/ml.

Recommended procedure:

Synthesis of Schiff base ligands:

N-(2-(7H-purin-6-ylimino)methyl)benzylidene)-7H-purin-6-mine (PMBPA) (L₁): A 25 ml of aqueous methanolic solution (1:1) of OPA (2.68 g, 0.02 Mol) has been added to the 25 ml of aqueous methanolic solution (1:1) of adenine (5.40 g 0.04 Mol) drop wise with constant stirring. Then the whole mixture have been stirred for about 2.5 h on a hot plate. The white colored product is filtered, washed with ethanol. Recrystallized from 3:1 water and 1,4-diaxan mixture and dried over vacuo. The purity of the product has been found to be TLC pure in 8:2 chloroform and methanol mixture. Its physical and analytical data are given below.

Yield 80 %; mp 285 °C; IR 3302, 2926 w, 1608, 1420, 1331 cm^-1; ¹H NMR (200MHz, CDCl₃) d in ppm 6.85-7.24 (4H, m, Ar-H), 7.42 (2H, s, Ar-H), 7.80 (2H, s, Ar-H), 7.92 (2H, s, NH), 8.20 (2H, s, CH=N); ¹³C NMR 114.52, 123.26, 129.56, 130.42, 131.64, 135.65, 156.86 (14C, Ar-C), 165.46 (2C, CH=N) 179.45 (2C, Ar-C). Anal. Found C, 58.66; H, 3.26; N, 38.00 %. Calcd. for C₁₈H₁₂N₁₀: C, 58.69; H, 3.28; N, 38.03 %, MS: [M]⁺at m/z 368 (43%),

N¹-(5-nitrophridyl)-N²-1-(-2-(-2-(5-nitro-2-pyridyl)aminoethyl)imino-methyl-phenyl)-methy-

lidene)-1,2-ethanediamine (NNIMED) (L₂): OPA (2.68 g, 0.02 Mol) in 30 ml aqueous methanolic solution (1:1) are added drop wise to 2-(2-aminoethyl amino)-5-nitro pyridine (7.28 g, 0.04 Mol.). Then the whole mixture has been stirred for about 1 h on a hot plate stirrer. The orange colored product is filtered, washed with ethanol. Recrystallized from methanol and diethyl ether. The product has been found to be TLC pure in 8:2 ethyl acetate and n-hexane mixture. Its physical and analytical data are given below.

Yield 72 %;  mp 128 °C; IR 3310, 3020 w, 1620, 1405, 1327, 1276 cm^-1; ¹H NMR (200MHz, CDCl₃) d in ppm 3.20 (4H, t, NH-CH₂), 3.48 (4H, t, =N-CH₂), 3.61 (2H, m, NH), 7.45-7.82 (8H, m, Ar-H), 8.20 (2H, s, Ar-H), 8.28 (2H, s, CH=N); ¹³C NMR 54.85 (2C, NH-CH₂), 57.42 (2C, =N-CH₂), 111.45, 129.56, 130.42, 132.22, 134.61, 135.65, 145.26, 164.74 (16C, Ar-C), 167.55 (2C, CH=N). Anal. Found C, 57.11; H, 4.76; N, 24.21 %. Calcd. for C₂₂H₂₂N₈O₄: C 57.14;H, 4.79;N, 24.23 %, MS: [M]⁺ at m/z 462 (31%).

Synthesis of metal complexes:

The complexes ML₁, ML₁(H₂O)₂, [ML₁(H₂O)₂]Cl and [ML₂Cl₂], [ML₂]Cl₂, [ML₂Cl₂]Cl have been prepared by the reaction of Schiff base ligands with the metal precursors/salts in a (1:1; L:M) molar ratio. 5 mmol of the metal precursor/salt CoCl₂.6H₂O, NiCl₂.6H₂O, CuCl₂.2H₂O, RhCl₃.3H₂O, PdCl₂.2H₂O, each dissolved in ethanol was added to 5 mmol of the ligand dissolved in ethanol, the resulting solutions have been stirred and then refluxed for 3–4 h., Concentrated to 5 ml under reduced pressure and a few ml of diethylether was added to initiate the crystallization. The resulting precipitate was separated by suction filtration, washed with diethylether, vaccum dried to get a crystalline compound and have been recrystallized using dichloromethane and diethyl ether solvent mixture. All the remaining nine metal complexes were synthesized in a similar manner according to the above procedure.

Scheme1: Synthetic route of Navel Schiff base ligand (L1) and its metal complexes.

Scheme 2: Synthetic route of Navel Schiff base ligand (L2) and its metal complexes.

Metal catalyzed oxidation method

In a 100 ml round bottom flask, 4 ml of DDI solution, 4 ml of hydrogen peroxide and [Pd(NNIMED)]Cl₂ (0.01 mmol) have been taken and the contents of the flask were refluxed for 30 min at 60 °C. The resultant solution was cooled and transferred into a 20 ml calibrated tube. Now, 2 ml of sulphanilic acid solution was added and the tube was heated for 5 min in boiling water bath. Pink color has been developed slowly. The tube was cooled and the total volume made up to 20 ml with double distilled water. The absorbance colored solution was scanned in the range of 400–800 nm and the λ_max value of the colored product has been found to be 520 nm. The amount of DDI formed was determined from its calibration curve derived in the range of 50–250 μg/ml.

RESULTS AND DISCUSSION:

In the present investigations, ten new Schiff base Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) complexes have been synthesized by treating CoCl₂.6H₂O, NiCl₂.6H₂O, CuCl₂.2H₂O, RhCl₃.3H₂O, PdCl₂.2H₂O, using non template method (Scheme 1 and 2) and all the complexes are stable in air and soluble in methanol. The purity of the Schiff base ligands were monitored by gas chromatography. The percentages of carbon, hydrogen and nitrogen were determined experimentally using CHN analyzer. The physical and analytical data for the newly synthesized compounds is in good agreement with the proposed molecular formula (Table-1).

Table 1:  Analytical, spectral and physical data of Schiff base Co(II),Ni(II),Cu(II),Rh(III) and Pd(II)metal complexes

	Schiff base ligands/Metal complexes	Color (Yield%)	lmax(nm)	ΛM (Ω^-1cm^2 mol^-1)	Found (Calcd(%)
					C	H	N	M
1	[Co(PMBPA)(H2O)2]	Light Purple(85)	1050,515,443	11.5	48.00 (48.01)	3.37 (3.39)	29.45 (29.47)	12.38 (12.40)
2	[Co(NNIMED)Cl2]	Pale Pink(89)	1062,520,464	8.4	44.60 (44.61)	3.72 (3.74)	18.91 (18.92)	9.92 (9.95)
3	[Ni(PMBPA)(H2O)2]	Pale Purple(86)	1077,728,410	21.6	48.00 (48.03)	3.38 (3.39)	29.46 (29.48)	12.33 (12.35)
4	[Ni(NNIMED)Cl2]	Orange(84)	1070,715,384	11.4	44.61 (44.63)	3.74 (3.75)	18.91 (18.93)	9.89 (9.91)
5	[Cu(PMBPA)]	Dark Blue(89)	680,500	15.6	51.40 (51.41)	2.70 (2.72)	31.53 (31.55)	14.30 (14.32)
6	[Cu(NNIMED]Cl2	Green(90)	685,509	52.7	44.25 (44.27)	3.70 (3.71)	18.75 (18.77)	10.62 (10.65)
7	[Rh(PMBPA)(H2O)2]Cl	Ash(85)	417,312	43.5	41.12 (41.14)	2.90 (2.91)	25.22 (25.25)	12.21 (12.19)
8	[Rh(NNIMED) Cl2]Cl	Orange(65)	432,322	48.3	39.33 (39.34)	3.28 (3.30)	16.67 (16.68)	10.25 (10.21)
9	[Pd(PMBPA)]	Cream(85)	485,315	14.8	46.87 (46.88)	2.46 (2.48)	28.76 (28.77)	21.85 (21.86)
10	[Pd(NNIMED)]Cl2	Yellow(75)	489,318	54.4	41.30 (41.30)	3.46 (3.47)	17.50 (17.51)	16.61 (16.63)

Table-2: IR Spectal data of  Navel Schiff base Co(II),Ni(II),Cu(II),Rh(III) and Pd(II) metal complexes

S. No.	Metal  complexes	Selected IR bands (cm^-1)
		uC=N	uNH	uM- H2O	uM-N	uM-Cl
1	[Co(PMBPA)(H2O)2]	1585	-	794	525	-
2	[Co(NNIMED)Cl2]	1592	3295	-	526	320
3	[Ni(PMBPA)(H2O)2]	1584	-	785	524	-
4	[Ni(NNIMED)Cl2]	1590	3292	-	525	315
5	[Cu(PMBPA)]	1580	-	-	525	-
6	[Cu(NNIMED]Cl2	1592	3295	-	528	-
7	[Rh(PMBPA)(H2O)2]Cl	1582	-	818	525	-
8	[Rh(NNIMED) Cl2]Cl	1594	3286	-	532	315
9	[Pd(PMBPA)]	1585	-	-	512	-
10	[Pd(NNIMED)]Cl2	1592	3286	-	526	-

Characterization of Novel Schiff base Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) metal complexes:

Infrared spectral analysis

The IR spectra of new Schiff base Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) complexes have been studied by comparing with the IR spectra of free Schiff base ligands to know the binding mode of metal and ligand (Table-2). In the IR spectra of the Schiff base ligands, a medium intensity u_C=N band is observed in the range of 1620–1608 cm^{-1 17}, which is shifted towards lower side about 1594–1580 cm^-1 in Schiff base metal complexes. This fact is further supported by the appearance of a medium intensity band in the region of 532–524 cm^-1 assignable to u_M–N vibration ¹⁹. The characteristic bands due to u_NH (heterocyclic ring) band due to in the spectra of ligand (L₂) was remained almost unchanged^20,21. It indicates that non-involvement of that nitrogen in bonding with metal center in the complexes. In the Schiff base ligand (L₁) u_N-H band was observed in the range of 3302 cm^-1.

In the Schiff base ligand (L₂) u_N-H band was observed in the range of 3310 cm^-1 and has been shifted towards lower side about 15 cm^-1 in metal complexes, thus lowering may be attributed to the decrease in electron density at the nitrogen atom. The IR spectra of metal complexes of 1, 3 and 7 bands were observed in the range of 818-785 cm^-1 indicates the presence of a coordinated water molecule in this complex. In metal complexes of 2, 4 and 8 a medium intensity bands observed in the region of 320-315 cm^-1 indicates the presence of two chlorides in trans position around the metal center ²². All the characteristic bands due to the aromatic rings²³ were also present in the expected regions in all the metal complexes. (Table-2).

NMR spectral analysis

Schiff base ligands and their Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) complexes have been characterized by ¹H NMR and ¹³C NMR spectroscopic data is shown in Table 3. A signal appeared in all the ligands of ¹H NMR spectrum is in the range of d 8.20-8.28 ppm is due to CH=N protons. However, in the spectra of Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) complexes the signal was moved to down field in the range of d 8.24–8.34 ppm suggests the coordination of imino nitrogen to metal ion²⁴.

Table-3 ¹H NMR and ¹³C NMR spectral data of Schiff base metal complexes

S.No	Schiff base metal complexes	^1H NMR peak position (d ppm)	^13C NMR peak position (d ppm)
1	[Co(PMBPA)(H2O)2]	6.83-7.21 (4H, m, Ar-H), 7.40 (2H, s, Ar-H), 7.84 (2H, s, Ar-H), 8.24 (2H, s, CH=N).	114.52, 123.26, 129.56, 130.42, 131.64, 135.65, 158.42 (14C, Ar-C), 167.86 (2C, CH=N) 179.45 (2C, Ar-C).
2	[Co(NNIMED)Cl2]	3.14 (4H, t, NH-CH2), 3.40 (4H, t, =N-CH2), 3.65 (2H, m, NH), 7.42-7.64 (8H, m, Ar-H), 8.22 (2H, s, Ar-H), 8.26 (2H, s, CH=N).	56.45 (2C, NH-CH2), 57.42 (2C, =N-CH2), 111.45, 129.56, 130.42, 132.22, 134.61, 135.65, 145.26, 164.74 (16C, Ar-C), 166.50 (2C, CH=N).
3	[Ni(PMBPA)(H2O)2]	6.82-7.22 (4H, m, Ar-H), 7.44 (2H, s, Ar-H), 7.84 (2H, s, Ar-H), 8.25 (2H, s, CH=N)	114.52, 123.26, 129.56, 130.42, 131.64, 135.65, 158.42 (14C, Ar-C), 167.42 (2C, CH=N) 180.05 (2C, Ar-C).
4	[Ni(NNIMED)Cl2]	3.15 (4H, t, NH-CH2), 3.41 (4H, t, =N-CH2), 3.66 (2H, m, NH), 7.42-7.62 (8H, m, Ar-H), 8.20 (2H, s, Ar-H), 8.26 (2H, s, CH=N)	56.45 (2C, NH-CH2), 57.42 (2C=N-CH2), 111.45, 129.56, 130.42, 132.22, 134.61, 135.65, 145.26, 164.74 (16C, Ar-C), 166.34 (2C, CH=N).
5	[Rh(PMBPA)(H2O)2]Cl	6.94-7.12 (4H, m, Ar-H), 7.40 (2H, s, Ar-H), 7.82 (2H, s, Ar-H), 8.24 (2H, s, CH=N)	114.84, 123.42, 129.46, 130.42, 131.64, 135.65, 156.82 (14C, Ar-C), 167.84 (2C, CH=N) 180.10 (2C, Ar-C).
6	[Rh(NNIMED) Cl2]Cl	3.24 (4H, t, NH-CH2), 3.56 (4H, t, =N-CH2), 3.62 (2H, m, NH), 7.75-8.02 (8H, m, Ar-H), 8.20 (2H, s, Ar-H), 8.34 (2H, s, CH=N)	55.42 (2C, NH-CH2), 57.40 (2C, =N-CH2), 112.34, 129.56, 130.42, 132.22, 134.62, 135.65, 145.26, 164.70 (16C, Ar-C), 166.62 (2C, CH=N).
7	[Pd(PMBPA)]	6.84-7.02 (4H, m, Ar-H), 7.42 (2H, s, Ar-H), 7.80 (2H, s, Ar-H), 8.26 (2H, s, CH=N).	114.20, 123.26, 129.56, 130.43, 131.64, 135.65, 157.44 (14C, Ar-C), 167.80 (2C, CH=N) 179.42 (2C, Ar-C).
8	[Pd(NNIMED)]Cl2	3.42 (4H, t, NH-CH2), 3.60 (4H, t, =N-CH2), 3.66 (2H, m, NH), 7.42-8.04 (8H, m, Ar-H), 8.20 (2H, s, Ar-H), 8.26 (2H, s, CH=N).	56.42 (2C, NH-CH2), 58.52 (2C, =N-CH2), 112.40, 129.56, 131.32, 132.20, 133.60, 135.52, 145.26, 164.74 (16C, Ar-C), 166.82 (2C, CH=N).

In the ligand (L₁) a broad signal observed in the range of d 7.80-7.92 ppm due to NH protons, this signal was disappeared in the metal complexes suggesting that the NH proton was deprotonated and nitrogen atom coordinated with metal ions. The signal due to NH proton was appeared in the region of d 3.20-3.48 ppm in the ligand (L₂) and this is shifted in the down field region in the range of d 3.40–3.60 ppm suggesting that the NH proton is in coordinated with metal ions. Multiplets ascertained in the range of d 6.82-8.20 ppm have been assigned to the aromatic protons²³. There is no appreciable change in the peak positions corresponding to aromatic protons²⁵. The ¹³C NMR spectra of all the ligands contain signal in the range of d 164.55–165.46 ppm²⁶ due to the presence of carbon, which is doubly bonded to nitrogen, a down field shift in peak position is observed in the range of d 166.34–167.86 ppm in complexes and this evidence confirms that the ligands coordinate through nitrogen atoms ²⁷. The ligand (L₂) which is having methylenic carbon adjacent to a nitrogen atom contains signal in the range of d 54.85-57.42 ppm. Indicate the presence of N-CH₂ linkage²⁸. Appreciable changes in peak positions were not observed with respect to aryl carbons²⁹

Electronic spectroscopic data

The electronic spectrum of all the complexes has been recorded in DMF. The electronic spectra of Co(II) complexes with these two ligands exhibit three d-d transition bands in the regions 1050-1062, 515-520 and 443-464 nm assigned to ⁴T_2g←⁴T_1g(F) (υ₁), ⁴A_2g←⁴T_1g(F) (υ₂) and ⁴T_1g(P)←⁴T_1g(F) (υ₃) transitions respectively (Table-1)³⁰.This indicates the octahedral geometry for all the Co(II) complexes. The octahedral geometry of Co(II) complexes is further supported by υ₂/υ₁ratio lying in the 2.0 to 2.03 range³¹. Ni(II) complexes exhibit octahedral geometry. They show three bands (u₁, u₂ and u₃) in 1020–1080, 640-730 and 360-410 nm (Table-1) regions assignable to ³A_2g(F)→³T_2g(F), ³A_2g(F)→³T_1g(F) and ³A_2g(F)→³T_1g(P) transitions, respectively. The octahedral geometry was further supported by u₂/u₁ ratio, which was lying in the range of 1.50-1.77. For the Cu(II) complexes showed an intensive band at about 680-740 nm attributed to ²A_1g←²B_1g transition and a broad band around 500-530 cm^-1 attributed to ²E_g←²B_1g transition of square planar environment³². Rh(III) complexes exhibit two main bands (u₁ and u₂) around 415-440 and 310-330 nm (Table-1) which were expected to be spin allowed transition and these obscured by charge transfer transitions. These bands correspond to ¹A_1g→¹T_1g and ¹A_1g→¹T_2g transitions, respectively, suggesting an octahedral geometry. The octahedral geometry was further supported by u₂ to u₁ ratio, which was lying in the range of 1.31-1.40³³. The Pd(II) complexes prepared have been found to show a broad d-d transition band in the region of 500-465 nm assignable to ¹B_1g←¹A_1g transition typical for the square planar geometry^34,35. Further a relatively strong charge transfer band has been observed in the spectra of all the Pd(II) complexes in the range of 320-280 nm. From the electronic spectral data and the diamagnetic behavior of the complexes, the square planar geometry has been proposed to all the Pd(II) complexes.

ESR spectral analysis:

The ESR spectra were recorded for Schiff base Cu(II) complexes at liquid nitrogen temperature (Table-4). The representative ESR spectra of [Cu(PMBPA)] and [Cu(NNIMED)]Cl₂ were recorded at liquid nitrogen temperature. The ESR spectrum of metal chelates provides information about hyperfine and super hyperfine structures which are important in studying the metal ion environment in complexes, i.e. the geometry, nature of the ligating sites from the Schiff base of metal and the degree of covalancy of the metal-ligand bonds. The 300 K spectra show an isotropic pattern, expected for Cu²⁺ in solution, but the spectra of the frozen solutions show the usual anisotropic pattern as expected for a powder sample. The absence of a half field signal at 1600 G, corresponding to the ∆Ms= ±2 transition, rules out any Cu–Cu interaction in the ESR spectra³⁴. The g-tensor values of the Cu(II) complexes can be used to derive the ground state. In square-planar complexes, the unpaired electron lies in the dx²-y² orbitals giving ²B_1g as the ground state with g_||> g_^> 2, while the unpaired electron lies in the dz² orbital giving ²A_1g as the ground state with g_^> g_||> 2. From the observed values it is clear that g_||» 2.20 > g_^» 2.05 > 2 and the ESR parameters of the complexes coincide well with related systems which suggest that the complexes have square-planar geometry and the systems are axially symmetric^36,37. This is also supported by the fact that the unpaired electron lies predominantly in the dx²-y² orbital^38–41, as was evident from the value of the exchange interaction term G, estimated from the expression: G=(g_||-2.0023)/(g_^-2.0023). These two compounds showed that g_||<2.3 indicating that the present complexes exhibit appreciable covalent nature⁴². The G values [G=(g_|| -2)/(g_^-2)] which measures the exchange interaction between the copper centers in polycrystalline compounds samples have been calculated. According to Hathaway, if G>4, it indicates that the exchange interaction is negligible and if G<4, it indicates a considerable exchange interaction in solid compounds⁴³. The calculated G values (Table 4) are larger than four, suggesting that there is no interaction between the copper centers⁴⁴. The broadening and splitting of the g_^ line is due to the overlap of g_|| and g_^ components, further indicating lowered site symmetry. Thus, the ESR data support the binding of the Cu (II) ion with Schiff base ligands in a square planar geometries.

Table-4  ESR spectral data of Schiff base Cu(II) complexes.

Cu(II) complexes	g||	g^	|g|avg	G
[Cu(PMBPA)]	2.206	2.041	2.096	5.260
[Cu(NNIMED)]Cl2	2.208	2.046	2.100	4.707

Table-5 Thermal analysis data of Schiff base Metal complexes.

Sl. No.	Metal Complexes	Decomposition temperature between 215-230°C	Decomposition temperature above 260°C	Pyrolysis percentage (Metal oxide) Found (Calcd.)
				Loss of weight on dehydration	Metal oxide formed
1.	[Co(PMBPA)(H2O)2]	223.5	296	7.52(7.58)	15.64(15.77)
2.	[Co(NNIMED)Cl2]	-	315	-	12.71(12.67)
3.	[Ni(PMBPA)(H2O)2]	215	295	7.92(7.83)	16.31(16.23)
4.	[Ni(NNIMED)Cl2]	-	318	-	12.73(12.65)
5.	[Cu(PMBPA)]	-	291	-	18.58(18.50)
6.	[Cu(NNIMED)] Cl2	-	324	-	13.26(13.34)
7.	[Rh(PMBPA)(H2O)2]Cl	225	290	6.72(6.67)	47.06(47.00)
8.	[Rh(NNIMED)Cl2]Cl	-	286	-	37.93(37.88)
9.	[Pd(PMBPA)]	-	263	-	26.02(25.93)
10.	[Pd(NNIMED)]Cl2	-	284	-	19.12(19.18)

Thermal analysis:

The thermal decomposition of the studied complexes presented characteristic pathways, depending on the nature of the ligands, as can be seen from the TG/DTA curves. These curves were obtained for the Schiff base Metal complexes over the temperature range 40–900 °C. In the Metal complexes 1, 3 and 7 two clear cut stages were observed, one is in the range of 215-225 °C corresponding to the loss of coordinated water molecule The percentage weight loss in this temperature range indicates that there are two water molecules in these complexes as coordinated water and the second is around 300 °C indicating the loss of organic moiety. In the remaining Schiff base metal complexes the absence of weight loss up to 230 °C indicates that there is no water molecule in these metal complexes. The sharp decomposition corresponding to the loss of the organic moiety can be seen in the DTA curves which contained one sharp exothermic peak falling in the range of 263–324 °C. The final product of decomposition of all the complexes above 450 °C corresponds to metal oxide. The thermo-gravimetric analysis data (Table-5) of the Metal complexes were obtained using less than 10 mg of the compound.

Magnetic and conductance measurements:

The magnetic susceptibility measurements have been carried out for Schiff base metal complexes. The magnetic properties depend on the ground and excited states of the metal complexes. The magnetic moments of Co(II), Ni(II) and Rh(III) metal complexes are in the range of 3.02-5.04 B.M. and thus confirm octahedral geometry around metal ion⁴⁵. These magnetic moment values are higher than spin only value indicating the contributions from orbital angular momentum values. The magnetic moment of Schiff base Cu(II) complexes at room temperature lie in the range of 1.91-1.98 B.M ²¹, corresponding to one unpaired electron. This indicates that these complexes are monomeric in nature. The magnetic susceptibility measurements have been carried out for Schiff base Pd(II) complexes and these compounds were found to be diamagnetic and hence Pd(II) ion is in the low spin configuration. The diamagnetic natures of complexes were further confirmed by the sharp well defined signals in the ¹HNMR spectra.

The molar conductance values for all the Schiff base metal complexes (10^-3 M) have been determined in dichloromethane⁴⁶. These values were found to below 8.4-21.6 ohm^-1cm² mol^-1 for compounds 1-5 and 9, indicating that non-electrolytic nature. For complexes 6 and 10, values are found to be 52.7-54.4 ohm^-1cm²mol^-1 and for the complexes 7 and 8 were found to be 43.5-48.3 ohm^-1cm²mol^-1 indicating 1:2 and 1:1 electrolytic nature respectively. The electrolytic natures of 6 and 10 and 7 and 8 were due to the presence of two and one chloride ion outside the coordination sphere respectively. The presence of chlorine ion in these compounds has been detected by the addition of silver nitrate reagent leading to the formation of white precipitate. (Table-1)

Mass spectral analysis:

The proposed molecular formulas of all the metal complexes were confirmed by comparing their molecular formula weights with m/z values. The molecular ion peaks at m/z (M⁺) 475 (1), 591(2), 460(3), 590(4), 429(5), 595(6), 540(7), 670(8), 472(9), 638(10). This data is in good agreement with the respective molecular formulae of metal complexes.

Catalytic application:

Development of catalytic oxidation method:

Didanosine (DDI) chemically known as 9-[(2R, 5S)-5-(hydroxymethyl)oxolan-2-yl]-6, 9-dihydro-3H-purin-6-one is an anti-retroviral drug ⁴⁷. DDI contains aliphatic alcoholic group and offers selective oxidation reactions. The oxidation of DDI by using novel Pd (II) catalyst (10) to yield its aldehydic product in the absence of co-oxidant. To produce a high yield of oxidation product ODDI, a continuous feed of hydrogen peroxide was employed ⁴⁸ in the presence of catalyst 10 and 3-5 ml of hydrogen peroxide was found to be adequate. To assess whether any direct oxidation occurred with hydrogen peroxide, it was added to DDI in the absence of above catalyst at 60 °C. The oxidation of DDI was started around 40 min and completed after 2.5 h. The yield of ODDI was found to be 80.21 %. But, in the presence of Pd(II) catalyst 10, the oxidation was started at about 20 min., completed within 30 min. and the yield of the oxidation product was found to be 92.46 % and 0.01 mmol of catalyst 10 were found to be optimized for the reaction. The best results were obtained when the temperature of reaction mixture was set to 70 °C. The role of co-oxidant viz. N-methyl morpholine-N-oxide, which is generally used for the oxidation of benzyl alcohol ⁴⁹, was also investigated. The percent yield of ODDI in the presence as well as in the absence of co-oxidant was found to be one and the same. Hence, co-oxidant was not involved in the present catalytic system. After completion of the oxidation of DDI, the resulting ODDI was cooled and its condensation was carried out with amino group compound sulfanilic acid ⁵⁰. Two ml of sulfanilic acid was found to be adequate for condensation. The color product wavelength value was found to be 520 nm. The colored product was stable up to one hour at room temperature⁵¹.

Product analysis:

To establish the structure of oxidized product, the IR, ¹H and ¹³C NMR spectra of DDI were compared with those of the oxidized product of DDI (ODDI). The IR spectrum of DDI shows a broad peak around 3390 cm¹ due to O–H stretching and which is disappeared in the ODDI and the appearance of a strong absorption band in ODDI around 1670 cm^-1 indicates the presence of C=O stretching of aldehyde after oxidation. The ¹H NMR spectrum of DDI shows a peak at d 4.36 ppm   corresponding to –OH proton. In the ¹H NMR spectrum of ODDI, these peaks were completely disappeared and a new peak was observed at d 9.62 ppm corresponding to the aldehydic proton. Oxidation of alcoholic group of DDI to aldehydic group is also confirmed by ¹³C NMR spectral analysis. The ¹³C NMR spectrum of DDI shows peaks at d 142.8, 135.2, 83.6, 85.7, 61.6, 30.8 and 21.0 ppm corresponding to C-2, C-8, C-1’, C-4’, C-5’, C-2’ and C-3’ carbons, respectively. However, in the ¹³C NMR spectrum of ODDI, the peak of C-5’ is shifted from d 61.6 to 180.0 ppm and the remaining peaks are almost unchanged. These results reveal the fact that the alcoholic group attached to C-5’ carbon is oxidized to aldehydic group. The mass spectrum of ODDI was shown molecular ion peak at m/z value of 235.2 (M⁺).

Catalytic cycle of Pd(II) complexes in the oxidation of DDI.

Chemistry of colored species and yields of oxidation products:

The condensation reaction between aldehyde group of ODDI with amino group of sulphanilic acid in acid medium with the elimination of water molecule (Scheme 3). The percent yields of ODDI with novel Pd(II) catalyst was determined spectrophotometrically. The yield of the oxidation product was appreciable amount (92.46 %).

Scheme 3: Colored product formed between ODDI and SA

Mechanism of catalytic cycle

A plausible mechanism is proposed for Pd(II) complex catalyzed oxidation of DDI (Scheme 4). Pd(II) oxidizes two moles of DDI containing alcoholic group to two molecules of ODDI having aldehydic groups by the loss of four hydrogen atoms in the presence of hydrogen peroxide. In this process, Pd(II) gains two electrons and converts to Pd(0) with the release of two chlorine atoms. Two moles each of hydrochloric acid and water generates as by products. Finally, Pd(0) complex reacts with two hydrochloric acid molecules in situ to regenerate the original Pd(II) complex with the evolution of hydrogen gas.

Scheme 4: Catalytic cycle of Pd(II) complexes in the oxidation of DDI.

Antibacterial activity

The ligands and their Co(II), Ni(II), Cu(II), Rh(III) and Pd(II) complexes were tested in vitro for their antibacterial activities against Bacillus subtilis as Gram-positive (G⁺) and Escherichia coli, as Gram-negative(G^-) pathogenic bacterial strains. Antifungal activities were evaluated against Aspergillus flavus and Fusarium oxysporum as fungus. The solvent, DMSO did not show any significant inhibitory effect against the tested organisms. The antibacterial and antifungal activities of the Schiff base ligands and their metal complexes were compared with standard antibiotics like ampicillin in the case of bacteria and fluconazole as a standard antifungal reference.

Preliminary screening for all the complexes have been performed at the fixed concentration of 1000 µg/ml. Inhibition was recorded by measuring the diameter of the inhibition zone at the end of 24 h for bacteria⁵¹. All the complexes of the tested series possessed good antibacterial activity against both G⁺ and G^- bacteria. The activities of all these complexes were further confirmed by determining the MIC values by liquid dilution method in which the effectiveness was observed at lower concentrations. The comparison of the MICs (in μg/mL) of all complexes and standard drugs against tested strains is presented in Fig.1 (Table-6). It was found that all the metal complexes show very good activity than ligands.

The antibacterial activity of Cu(II), Co(II), Ni(II) and Pd(II) complexes are higher than that of Rh(III) complexes. The antibacterial activity of the metal complexes increases with increase in concentration. It is suggested that the complexes have antibacterial activity, inhibit the multiplication process of the microbes by blocking their active sites. The bioactivity of the ligand and its metal complexes was found to be in the order: The higher activity of Cu(II) complexes can be explained as, on chelation the polarity of Cu(II) ion is found to be reduced to a greater extend due to the overlap of the ligand orbital and partial sharing of the positive charge of the copper ion with donor groups. Therefore, Cu(II) ions are adsorbed on the surface of the cell wall of microorganisms^52,53. The adsorbed Cu(II) ions disturb the respiratory process, thus blocking the synthesis of proteins. This, in turn, restricts further growth of the organisms. The antifungal activity of Cu(II) complexes are found to be higher than that of the free ligand as well as other metal complexes. The biological activity is found to follow the order Cu(II)>Co(II)>Ni(II)>Pd(II)>Rh(III)> Ligands.

Table 6: Antimicrobial Activity of the Schiff Base Ligands L₁ (pmbpa), L₂ (nnimed), and their Co(II), Ni(II), Cu(II), Rh(III) and Pd (II) complexes against standard drugs.

Sl.No.	Ligand /Metal Complexes	Zone of Inhibition (mm)
		Gram-positive bacteria (G^+)	Gram-negative bacteria (G^-)	Fungus
		B.subtilis	E.coli	Aspergillus flavus	Fusarium oxysporum
L1	pmbpa	18	22	17	15
1	[Co(pmbpa) (H2O)2]	33	34	21	19
2	[Ni(pmbpa)(H2O)2]	32	30	19	17
3	[Cu(pmbpa)]	33	32	23	20
4	[Rh(pmbpa)(H2O)2]Cl	27	24	21	18
5	[Pd(pmbpa)]	28	26	18	15
L2	nnimed	14	20	18	15
6	[Co(nnimed) Cl2]	22	25	23	22
7	[Ni(nnimed)Cl2]	20	22	20	21
8	[Cu(nnimed)]Cl2	24	23	25	23
9	[Rh(nnimed)Cl2]Cl	17	21	18	20
10	[Pd(nnimed)] Cl2	26	28	19	20
	Ampicillin	35	37	-	-
	Fluconazole	-	-	33	31

Fig.1  Comparison of MICs values (inμg/mL) of ligands,complexes and standard drugs against different bacteria and fungi.

CONCLUSION

In this present studies, the non-template synthesis of ten new Schiff base complexes were synthesized. The analytical data show the presence of one metal ion per molecule and suggest a mononuclear structure for these complexes. The magnetic moment values and electronic spectroscopic data are in the favour of octahedral geometry for Co(II), Ni(II), and Rh(III) complexes and square planar geometry for Pd(II) and Cu(II) complexes. In 1, 3, and 7 Schiff base complexes ligands coordinate through four nitrogen atoms and two water molecules. In Schiff base complexes 2, 4 and 8 the ligands coordinate through four nitrogen atoms and two chloride ions. The molar conductance values for compounds 1-5 and 9 indicating non-electrolytic nature and for compounds 6-8 and 10 indicating electrolytic nature. Highly efficient Schiff base Pd (II) complex was used for the oxidation of DDI via alcoholic group. The catalytic method allows the rapid synthesis of carbonyl derivatives. This is an environmentally friendly method, simple to set-up, requires short reaction time, produces high product yields and does not require co-oxidant. The reusability of the catalyst is the most significant aspect of this method. All the synthesized ligands and metal complexes were screened for their antibacterial and antifungal activities by MIC method. The antibacterial and antifungal activity of Cu(II), Co(II), Ni(II), Rh(III) and Pd(II) complexes are to follows the order Cu(II)> Co(II)> Ni(II)> Pd(II)> Rh(III)> Ligands.

ACKNOWLEDGMENTS:

Authors are thankful to Director, Indian Institute of Chemical Technology (IICT), Hyderabad to providing spectral data and Head, University of Hyderabad, Hyderabad to providing ESR spectra. Director, SAIF, Indian Institute of Technology Madras (IIT Madras), Chennai for providing magnetometer.

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Received on 28.01.2016         Modified on 17.02.2016

Accepted on 17.03.2016         © AJRC All right reserved

Asian J. Research Chem. 9(3): Mar., 2016; Page 133-144

DOI: 10.5958/0974-4150.2016.00023.7